WO2022155656A1 - Compositions cosmétiques - Google Patents

Compositions cosmétiques Download PDF

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Publication number
WO2022155656A1
WO2022155656A1 PCT/US2022/070171 US2022070171W WO2022155656A1 WO 2022155656 A1 WO2022155656 A1 WO 2022155656A1 US 2022070171 W US2022070171 W US 2022070171W WO 2022155656 A1 WO2022155656 A1 WO 2022155656A1
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Prior art keywords
tpm
liposomal composition
topical
final formulation
skin
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PCT/US2022/070171
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English (en)
Inventor
George P. Majewski
Christine CRANE
John Simon CRAW
Gabriele DI FIORE
Dzung Q. LE
Olga Dueva-Koganov
Robert Bianchini
Angela M. RIVERA
Original Assignee
Rodan & Fields, Llc
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Publication of WO2022155656A1 publication Critical patent/WO2022155656A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/676—Ascorbic acid, i.e. vitamin C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/678—Tocopherol, i.e. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/805—Corresponding aspects not provided for by any of codes A61K2800/81 - A61K2800/95

Definitions

  • Embodiments disclosed herein are directed to tocopherol phosphate mixture (TPM) liposomal compositions comprising a liposome, made of a mixture of tocopherol phosphate derivatives, having a lipid bilayer and an internal compartment, a polar solvent system containing a polar solvent 1, a polar solvent 2, and a Ci-Ce alcohol, a neutralizing base, and a water soluble phase, wherein one or more lipophilic ingredients is entrapped in the lipid bilayer of the liposome, and one or more water soluble ingredients is dissolved in the water soluble phase in the internal compartment of the liposome, and wherein the TPM liposomal composition has a pH of about 4.5 to about 5.
  • Embodiments disclosed herein are directed to topical final formulations comprising about 0.1% to about 40% of a TPM liposomal composition by weight of the topical final formulation, an additive, water, and a cosmetically acceptable excipient.
  • Embodiments are directed to methods of improving the look of skin in a human subject in need thereof comprising topically administering to the skin of the subject a topical final formulation comprising about 0.1% to about 40% of a TPM liposomal composition by weight of the topical final formulation, an additive, water, and a cosmetically acceptable excipient.
  • the skin is the neck or decolletage.
  • Embodiments are directed to methods of increasing expression of an extracellular matrix protein in skin of a subject in need thereof comprising administering a topical final formulation comprising about 0.1% to about 40% of a TPM liposomal composition by weight of the topical final formulation, an additive, water, and a cosmetically acceptable excipient.
  • Embodiments are directed to methods of improving a keloid scar in a subject in need thereof comprising topically administering a topical final formulation comprising about 0.1% to about 40% of a TPM liposomal composition by weight of the topical final formulation, an additive, water, and a cosmetically acceptable excipient.
  • Embodiments are directed to methods of improving the appearance of aged skin in a subject in need thereof comprising topically administering a topical final formulation comprising about 0.1% to about 40% of a TPM liposomal composition by weight of the topical final formulation, an additive, water, and a cosmetically acceptable excipient.
  • Embodiments are directed to methods of improving the appearance of various keratinous fibers in a subject in need thereof comprising topically administering a topical final formulation comprising about 0.1% to about 40% of a TPM liposomal composition by weight of the topical final formulation, an additive, water, and a cosmetically acceptable excipient.
  • Embodiments are directed to methods of improving the contour of the neck or jawline in a subject in need thereof comprising topically administering a topical final formulation comprising about 0.1% to about 40% of a TPM liposomal composition by weight of the topical final formulation, an additive, water, and a cosmetically acceptable excipient.
  • Embodiments are directed to methods of decreasing the appearance of cellulite in a subject in need thereof comprising topically administering a topical final formulation comprising about 0.1% to about 40% of a TPM liposomal composition by weight of the topical final formulation, an additive, water, and a cosmetically acceptable excipient.
  • Embodiments are directed to methods of increasing expression of an extracellular matrix protein in a model system based on a cell-based assay using adult human dermal fibroblasts or in a 3-dimensional reconstructed skin model comprising administering a TPM liposomal composition comprising a liposome, made of a mixture of tocopherol phosphate derivatives, having a lipid bilayer and an internal compartment, a polar solvent system containing a polar solvent 1, a polar solvent 2, and a Ci-Ce alcohol, a neutralizing base, and a water soluble phase, wherein one or more lipophilic ingredients is entrapped in the lipid bilayer of the liposome, and one or more water soluble ingredients is dissolved in the water soluble phase in the internal compartment of the liposome, and wherein the TPM liposomal composition has a pH of about 4.5 to about 5.
  • Embodiments are directed to methods for preparing a TPM liposomal composition
  • a polar solvent system such as dimethyl isosorbide (DMI) and pentylene glycol
  • a polar solvent system such as dimethyl isosorbide (DMI) and pentylene glycol
  • a tocopherol phosphate derivative ingredient to the mixture from step a) once temperature reaches about 57.9°C to about 61 °C, heating and maintaining the temperature of the resulting mixture to between about 57.9°C to about 61°C until all contents melted
  • a polar solvent system such as dimethyl is
  • Figure 1A is a three-dimensional schematic of a liposome showing the compartments as described herein.
  • Figure IB is a two-dimensional schematic of the same.
  • Figure 2 demonstrates the transdermal penetration of 0.5% resveratrol dimethyl ether prepared in the 4 test samples.
  • Figure 3 demonstrates the time-course permeation of resveratrol dimethyl ether through a Strat-M Membrane using illumination with UVB light after 0.5 min., 5 min. and 15 min.
  • Figure 4 shows the results of tests performed to demonstrate resveratrol dimethyl ether permeation into Strat-M membranes.
  • the epidermis the outer layer of the skin, protects from the environment and resists topically applied substances.
  • a range of substances have been developed which penetrate the skin in a variety of methods. For example, hydroxosomes penetrate the epidermis and dermis of the skin transappendageally (through hair follicle and sweat gland); nanosomes, nanoemulsions, or liposomes penetrate the epidermis and dermis of the skin transcellularly (passing from cell to cell, through adjacent cell membranes), and humectant hydration penetrates the epidermis and dermis of the skin paracellularly (passing through the intercellular space between cells).
  • the thickness of the epidermis and dermis of the skin is quite different over the entire body.
  • the epidermis of the neck and decolletage is about two fold the thickness of the eyelid, however, the dermis of the skin of the neck is thinner than most other facial areas. Accordingly, delivering cosmetic actives to the neck skin area maybe challenging due to the epidermal thickness.
  • the neck and decolletage dermis is thinner than most facial skin and with age the structure may be more prone to sagging and deep wrinkles as the connective tissue weakens. Fat deposits in the hypodermis (located below the dermis) are likely to protrude through the dermis/epidermis for a stronger visible impact, creating a cellulite-like effect.
  • a capable delivery system can be employed with cosmetic ingredients which can support the extracellular matrix (ECM) constituents (i.e. collagen and elastin) and induce triglyceride (fat) metabolism (cyclic AMP).
  • ECM extracellular matrix
  • cyclic AMP triglyceride
  • alpha-tocopheryl phosphate (TP) and di-alpha-tocopheryl phosphate (T2P) are two phosphorylated forms of vitamin E which form tocopheryl phosphate mixture (TPM), which produce small particle size micelles or vesicles.
  • TPM is useful delivery carrier for agents used to improve skin quality and/or which have anti-aging qualities and/or anti-cellulite properties.
  • Embodiments described herein are directed to TPM liposomal compositions and topical final formulations containing said TPM liposomal compositions which effectively penetrate the skin, including the skin of the neck and decolletage, and to deliver cosmetic agents to improve the look and feel of the skin.
  • administer refers to directly administering a composition, including an agent of interest, to the skin of a subject.
  • excipients encompasses carriers and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a cosmetic or other agent across a tissue layer such as the stratum comeum or stratum spinosum.
  • transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
  • the transitional phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim.
  • the transitional phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed subject matter.
  • the term comprising is used as the transition phrase, such embodiments can also be envisioned with replacement of the term “comprising” with the terms “consisting of’ or “consisting essentially of.”
  • cosmetic means an agent utilized, and/or intended to be applied to the human body for cleansing, beautifying, promoting attractiveness, altering the appearance of the skin, or any combination thereof.
  • keratinous fiber refers to any tissue which contain keratin as a fibrous structural protein, including, but not limited to, skin, hair, and nails.
  • liposome as used herein interchangeably with “vesicle” means an artificial vesicle composed of one or more concentric phospholipid-like bilayers (as provided in Figure 1A or IB), used especially to deliver microscopic substances (such as cosmetic additives or other additives) to the skin.
  • the hydrophobic tocopherol phosphate derivative/vitamin E portions associate in an aqueous environment to form closed, spherical bilayers encapsulating hydrophobic components of interest within the bilayer compartment.
  • the enclosed aqueous volume or water phase is within the internal compartment where the hydrophilic ingredients of interest are dissolved.
  • compositions, dosage forms, etc are suitable for use in contact with the tissues of human beings and/or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • upregulation refers to the process of increasing the response to a stimulus. Specifically, it refers to the increase in a cellular response to a molecular stimulus due to increase in the number of receptors on the cell surface. In the biological context of organisms' production of gene products, upregulation is the process by which a cell increases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus.
  • a cellular component such as RNA or protein
  • subject may be taken to mean any living organism which may be administered compounds or compositions provided for herein.
  • the term “subject” may comprise, but is not limited to, any non-human mammal, primate or human.
  • the subject is an adult, child or infant.
  • the subject is a human.
  • topically and “topical” refers to application of the compositions described herein to the surface of the skin, mucosal cells, tissues, and/or keratinous fibers.
  • TPM refers to a mixture of alpha-tocopheryl phosphate (TP) and di-alpha-tocopheryl phosphate (T2P) which are two phosphorylated forms of vitamin E which form tocopheryl phosphate mixture (TPM).
  • TP alpha-tocopheryl phosphate
  • T2P di-alpha-tocopheryl phosphate
  • TPM acts as a liposome to encapsulate both hydrophobic and hydrophilic molecules at high efficiency.
  • TPM acts as a liposome to encapsulate both hydrophobic and hydrophilic molecules at high efficiency.
  • TPM acts as a liposome to encapsulate both hydrophobic and hydrophilic molecules at high efficiency.
  • TPM acts as a liposome to encapsulate both hydrophobic and hydrophilic molecules at high efficiency.
  • TPM acts as a liposome to encapsulate both hydrophobic and hydrophilic molecules at high efficiency.
  • TPM acts as a liposome to
  • treating refers generally to include the administration of a compound or composition which reduces a scar, decreases the appearance of cellulite, or enhances the texture, appearance, color, sensation, or hydration of the intended tissue treatment area of the tissue surface in a subject relative to a subject not receiving the compound or composition. This can include reversing, reducing, or arresting the unwanted symptoms, to improve or stabilize a subject’s skin.
  • compositions are cosmetic compositions and are for cosmetic use. In any of the embodiments described herein, the compositions are not pharmaceutical compositions and are not for pharmaceutical use.
  • Embodiments disclosed herein are directed to a TPM liposomal composition
  • a TPM liposomal composition comprising: a liposome, made of a mixture of tocopherol phosphate derivatives, having a lipid bilayer and an internal compartment, a polar solvent system containing a polar solvent 1, a polar solvent 2, and a Ci-Ce alcohol, a neutralizing base, and a water soluble phase, wherein one or more lipophilic ingredients is entrapped in the lipid bilayer of the liposome, and one or more water soluble ingredients is dissolved in the water soluble phase in the internal compartment of the liposome, and wherein the TPM liposomal composition has a pH of about 4.5 to about 5.
  • water soluble components of the polar solvent system will be in the water soluble phase and may diffuse out of the liposome.
  • water soluble Ci-Ce alcohols will be in the water soluble phase and may diffuse out of the liposome.
  • the neutralizing base will be in the water soluble phase.
  • the liposome is a multilamellar vesicle (MLV), a small unilamellar vesicle (SUV), or a large unilamellar vesicle (LUV).
  • MLV multilamellar vesicle
  • SUV small unilamellar vesicle
  • LUV large unilamellar vesicle
  • Multilamellar vesicles (MLV) have several lipid bilayers, i.e. liposomes within liposomes.
  • Unilamellar vesicles, SUV or LUV have a single lipid bilayer.
  • the liposomes can be used to facilitate topical delivery and stability of components of the TPM liposomal composition.
  • the liposomes have a particle size range of about 100 nm to about 1000 nm, with a median particle size of about 300 nm to about 700 nm. In some embodiments, the particle size is determined by Method A as described herein.
  • the polar solvent system which comprises a polar solvent 1, a polar solvent 2, and a Ci-Ce alcohol, is present in an amount of about 15% to about 20% by weight of the TPM liposomal composition. In certain embodiments, the polar solvent system is present in an amount of about 18.08% by weight of the TPM liposomal composition. In certain embodiments, the polar solvent system is present in an amount of about 16% by weight of the TPM liposomal composition.
  • the Ci-Ce alcohol is selected from the group consisting of methanol, ethanol, 1 -propanol, and isopropanol. In preferred embodiments, the Ci-Ce alcohol is ethanol.
  • the Ci-Ce alcohol is present in an amount of about 5% to about 10% by weight of the TPM liposomal composition. In preferred embodiments, the Ci-Ce alcohol is at about 7% by weight of the TPM liposomal composition. In preferred embodiments, the Ci-Ce alcohol is at about 8% by weight of the TPM liposomal composition. Without being bound by theory, Ci-Ce alcohol within the disclosed ranges is required to get efficient formation of the liposomes without precipitation within the composition.
  • the polar solvent 1 and the polar solvent 2 of the polar solvent system is present in an amount of about 8% to about 12% by weight of the TPM liposomal composition. In certain embodiments, the polar solvent system is present in an amount of about 10.08% by weight of the TPM liposomal composition. In preferred embodiments, the polar solvent system is present in an amount of about 9% by weight of the TPM liposomal composition.
  • the polar solvent 1 and the polar solvent 2 of the polar solvent system are selected from the group consisting of a polyol, a mono-alkyl isosorbide ether, di-alkyl isosorbide ether, and combinations thereof.
  • the polyol is pentylene glycol.
  • the di-alkyl isosorbide ether is dimethyl isosorbide.
  • the polar solvent 1 is pentylene glycol (PG).
  • the polar solvent 2 is dimethyl isosorbide (DMI).
  • the ratio of polar solvent 1 to polar solvent 2 is selected from the group consisting of 3: 2, 2.5: 1.5, 2: 1, 2: 1.5, 1.5: 1, and 1: 1. In certain embodiments, the ratio of polar solvent 1 to polar solvent 2 is 2.27: 1. In certain embodiments, the ratio of polar solvent 1 to polar solvent 2 is 1.47: 1. In certain embodiments, the ratio of polar solvent 1 to polar solvent 2 is 2: 1.
  • the ratio of the Ci-Ce alcohol to the polar solvent 1 to the polar solvent 2 is selected from the group consisting of 4:4:1, 3: 2: 1, 2.59: 2.27: 1, 2.3: 2: 1, 2: 1.5: 1, 1.71: 1.47: 1, and 1: 1: 1.
  • the ratio of the Ci-Ce alcohol to the polar solvent 1 to the polar solvent 2 is 2.59: 2.27: 1.
  • the ratio of the Ci-Ce alcohol to the polar solvent 1 to the polar solvent 2 is 1.71: 1.47: 1.
  • the ratio of the Ci- Ce alcohol to the polar solvent 1 to the polar solvent 2 is 2.3: 2: 1.
  • the polar solvent 1 is present in an amount of about 5% to about 10% by weight of the TPM liposomal composition. In certain embodiments, the polar solvent 1 is present in an amount of about 6% to about 7.5% by weight of the TPM liposomal composition. In preferred embodiments, the polar solvent 1 is present in an amount of about 6% by weight of the TPM liposomal composition. In preferred embodiments, the polar solvent 1 is present in an amount of about 7% by weight of the TPM liposomal composition.
  • the polar solvent 2 is present in an amount of about 2% to about 6% by weight of the TPM liposomal composition. In certain embodiments, the polar solvent 2 is present in an amount of about 3% to about 4% by weight of the TPM liposomal composition. In preferred embodiments, the polar solvent 2 is present in an amount of about 3% by weight of the TPM liposomal composition. In preferred embodiments, the polar solvent 2 is present in an amount of about 3.08% by weight of the TPM liposomal composition.
  • the solvent system comprises about 7% pentylene glycol, about 3.08% dimethyl isosorbide, and about 8% ethanol.
  • the solvent system comprises about 6% pentylene glycol, about 3% dimethyl isosorbide, and about 7% ethanol.
  • the mixture of tocopherol phosphate derivatives is selected from the group consisting of alpha tocopherol phosphate derivatives, beta tocopherol phosphate derivatives, gamma tocopherol phosphate derivatives, and delta tocopherol phosphate derivatives in enantiomeric and racemic forms.
  • the mixture of tocopherol phosphate derivatives is a mono-tocopheryl phosphate derivative and a di-tocopheryl phosphate derivative.
  • the mixture of tocopherol phosphate derivatives comprises an alpha-tocopheryl phosphate (TP) and a di-alpha- tocopheryl phosphate (T2P).
  • the mixture of alpha-tocopheryl phosphate (TP) and a di-alpha-tocopheryl phosphate (T2P), also known as TPM the ratio of TP:T2P is in a range of about 4: 1 to about 1 : 1. In certain embodiments, the ratio of TP:T2P is selected from the group consisting of about 1.25:1, about 1.75:1, about 2.5:1, and about 3.5:1.
  • the mixture of tocopherol phosphate derivatives is present in an amount of about 1.5% to about 5% by weight of the TPM liposomal composition. In certain embodiments, the mixture of tocopherol phosphate derivatives is present in an amount of about 2.5% by weight of the TPM liposomal composition. In certain embodiments, the mixture of tocopherol phosphate derivatives is present in an amount of about 2.7% by weight of the TPM liposomal composition. In certain embodiments, alpha- tocopheryl phosphate (TP) is in an amount of about 0.75% to about 1.05% by weight of the TPM liposomal composition or about 2.5% to about 3.5% by weight of the TPM liposomal composition.
  • TP alpha- tocopheryl phosphate
  • di-alpha-tocopheryl phosphate is in an amount of about 0.3% to about 0.6% by weight of the TPM liposomal composition or about 1% to about 2% by weight of the TPM liposomal composition.
  • the one or more lipophilic ingredients (which may also be referred to as the hydrophobic ingredients) is selected from the group consisting of a hydrophobically modified amino acid, a hydrophobically modified vitamin, a retinoid, a resveratrol derivative, a fatty acid, a fatty ester, and combinations thereof.
  • the one or more lipophilic ingredients includes lipid soluble ingredients dissolved in fatty acids or fatty acid esters.
  • the hydrophobically modified amino acid is hydrophobically modified proline.
  • the hydrophobically modified amino acid is dipalmitoyl hydroxyproline.
  • the hydrophobically modified vitamin is a hydrophobically modified ascorbic acid.
  • the hydrophobically modified ascorbic acid is 3-O-cetyl ascorbic acid.
  • the retinoid is selected from the group consisting of retinaldehyde, ester of retinoic acid, hydroxypinacolone retinoate, retinyl palmitate, ali tretinoin (9-cis-retinoic acid), tretinoin (all-trans-retinoic acid), isotretinoin (13-cis-retinoic acid), etretinate, acitretin, adapalene, bexarotene, tazarotene, and derivatives and combinations thereof.
  • the retinoid is hydroxypinacolone retinoate.
  • the one or more lipophilic ingredients is a blend of pterostilbene (resveratrol dimethyl ether) and xymenynic acid dissolved in glyceryl linoleate and glyceryl linolenate.
  • the one or more lipophilic ingredients is present in an amount of about 0.1% to about 5% by weight of the TPM liposomal composition. In certain embodiments, the one or more lipophilic ingredients is present in an amount of about 0.1% to about 1% by weight of the TPM liposomal composition. In some embodiments, the one or more lipophilic ingredients is present in an amount of about 0.12% by weight of the TPM liposomal composition. In some embodiments, the one or more lipophilic ingredients are present in an amount of about 0.5% by weight of the TPM liposomal composition. In some embodiments, the one or more lipophilic ingredients is present in an amount of about 0.62% by weight of the TPM liposomal composition.
  • the one or more lipophilic ingredients is present in an amount of about 1.0% by weight of the TPM liposomal composition. In some embodiments, the one or more lipophilic ingredients is present in an amount of about 1.5% by weight of the TPM liposomal composition. In some embodiments, the one or more lipophilic ingredients is present in an amount of about 5% by weight of the TPM liposomal composition.
  • the neutralizing base is an organic base.
  • the organic base is selected from the group consisting of tromethamine, L- arginine, niacinamide, and combinations thereof.
  • the organic base is tromethamine.
  • the neutralizing base is an inorganic base.
  • the inorganic base is sodium hydroxide (NaOH).
  • the base is present in an amount of about 0.1% to about 1% by weight of the TPM liposomal composition. In some embodiments, the base is present in an amount of about 0.2% by weight of the TPM liposomal composition. In some embodiments, the base is present in an amount of about 0.3% by weight of the TPM liposomal composition.
  • the water soluble phase is present in an amount of about 70% to 85% by weight of the TPM liposomal composition. In certain embodiments, the water soluble phase comprises water in an amount of about 82.8% by weight of the TPM liposomal composition. In certain embodiments, the water soluble phase comprises water in an amount of about 77% by weight of the TPM liposomal composition. In certain embodiments, the water soluble phase comprises water in an amount of about 76% by weight of the TPM liposomal composition. In certain embodiments, the water soluble phase comprises water in an amount of about 75% by weight of the TPM liposomal composition. In certain embodiments, the water soluble phase comprises water in an amount of about 74% by weight of the TPM liposomal composition. In certain embodiments, the water soluble phase comprises water in an amount of about 73% by weight of the TPM liposomal composition.
  • the one or more water soluble ingredients is a water soluble amino acid, a water soluble vitamin, protein, xanthine, or combinations thereof.
  • the water soluble amino acid is selected from the group consisting of arginine, histidine, glycine, proline, and combinations thereof.
  • the water soluble amino acid is L-arginine.
  • the water soluble vitamin is selected from the group consisting of niacinamide, 3-O-ethyl ascorbic acid, vitamin C, and combinations thereof.
  • the water soluble protein is selected from the group consisting of, camosine, dipeptide-2, tetrapeptide-21, tripeptide-3, tetrapeptide-4, copper tetrapeptide, acetyl dipeptide- 1 cetyl ester, and combinations thereof.
  • the water soluble ingredient includes butylene glycol, sorbitan laurate, hydroxyethylcellulose, and acetyl dipeptide- 1 cetyl ester.
  • the xanthine is selected from the group consisting of methylxanthine, 1,3-dimethylxanthine (also known as theophylline), caffeine, and combinations thereof.
  • the one or more water soluble ingredients is present in an amount of about 0.1 % to about 4% by weight of the TPM liposomal composition. In some embodiments, the one or more water soluble ingredients is present in an amount of about 0.5% by weight of the TPM liposomal composition. In some embodiments, the one or more water soluble ingredients is present in an amount of about 1.0% by weight of the TPM liposomal composition. In some embodiments, the one or more water soluble ingredients is present in an amount of about 2.5% by weight of the TPM liposomal composition.
  • the TPM liposomal composition further comprises a humectant.
  • the humectant is selected from the group consisting of glycerin, diglycerin, betaine, diols, propylene glycol, butylene glycol, pentylene glycol, propanediol, 1,2-hexanediol, D-ribose, glucose, sorbitol, dextrose, urea, 2-Pyrrolidone-5- Carboxylic Acid and related salts, sea salt, inorganic salts of citric acid, inorganic salts of lactic acid, ectoin, lactic acid, betaine, glycolic acid, lactobionic acid, and any combination thereof.
  • the humectant is glycerin.
  • the humectant is in the water soluble phase.
  • the humectant is present in an amount of about 0.1% to about 5% by weight of the TPM liposomal composition. In some embodiments, the humectant is present in an amount of about 2.0% by weight of the TPM liposomal composition.
  • the TPM liposomal composition further comprises a gelling agent.
  • the gelling agent is in the water phase.
  • the gelling agent is selected from the group consisting of xanthan gum, gellan gum, carrageenan, biosaccharide gum-I, sclerotium gum, pectin, pullulan, guar gum, gum arabic, chondroitin, sulfate, alginic acid, sodium hyaluronate, hydrolyzed hyaluronic acid sodium polyglutamate, chitin, chitosan, starch, polyacrylate crosspolymer-6 (SepiMax Zen), and combinations thereof.
  • the gelling agent is xanthan gum.
  • the gelling agent is present in an amount of about 0.1% to about 1% by weight of the TPM liposomal composition. In some embodiments, the gelling agent is present in an amount of about 0.2% by weight of the TPM liposomal composition. In some embodiments, the gelling agent is present in an amount of about 0.3% by weight of the TPM liposomal composition.
  • a TPM liposomal composition comprises: a liposome, made of a mixture of tocopherol phosphate derivatives, having a lipid bilayer and an internal compartment, a polar solvent system containing pentylene glycol, dimtheyl isosorbide, and ethanol, tromethamine or sodium hydroxide as a neutralizing base, and a water soluble phase, wherein one or more lipophilic ingredients is entrapped in the lipid bilayer of the liposome, and one or more water soluble ingredients is dissolved in the water soluble phase in the internal compartment of the liposome, and wherein the TPM liposomal composition has a pH of about 4.5 to about 5.
  • a TPM liposomal composition comprises: a liposome, made of a mixture of tocopherol phosphate derivatives, having a lipid bilayer and an internal compartment, a polar solvent system containing about 6% pentylene glycol, about 3% dimtheyl isosorbide, and about 7% ethanol, about 0.2% sodium hydroxide (a 25% solution) as a neutralizing base, and a water soluble phase, wherein one or more lipophilic ingredients is entrapped in the lipid bilayer of the liposome, and one or more water soluble ingredients is dissolved in the water soluble phase in the internal compartment of the liposome, and wherein the TPM liposomal composition has a pH of about 4.5 to about 5.
  • a TPM liposomal composition comprises: a liposome, made of a mixture of tocopherol phosphate derivatives, having a lipid bilayer and an internal compartment, a polar solvent system containing about 7% pentylene glycol, about 3.08% dimtheyl isosorbide, and about 8% ethanol, about 0.3% tromethamine as a neutralizing base, and a water soluble phase, wherein one or more lipophilic ingredients is entrapped in the lipid bilayer of the liposome, and one or more water soluble ingredients is dissolved in the water soluble phase in the internal compartment of the liposome, and wherein the TPM liposomal composition has a pH of about 4.5 to about 5.
  • Embodiments disclosed herein are directed to a topical final formulation comprising: a TPM liposomal composition as described herein, an additive, a solvent, and a cosmetically acceptable excipient, wherein the TPM liposomal composition is present in an amount of about 0.1% to about 40% by weight of the topical final formulation.
  • the TPM liposomal composition described herein is part of a topical final formulation at about 1% to about 30%.
  • the TPM liposomal composition described herein is part of a topical final formulation at about 20%.
  • the TPM liposomal composition described herein is part of a topical final formulation at about 10%.
  • the topical final formulation is formulated in a form selected from the group consisting of a cream, solution, emulsion, semi-solid, jelly, paste, gel, hydrogel, ointment, lotion, emulsion, foam, mousse, liquid, suspension, or dispersion.
  • the topical final formulation is formulated in a product selected from the group consisting of neck cream, neck lotion, body lotion, body cream, face lotion, face cream, eye lash treatment, hair moisturizer, hair conditioner, cellulite treatment, nail conditioner, gel, emulsion, silicone gel, water gel, oil-in-water emulsion, or water-in-oil emulsion.
  • the solvent is selected from the group selected from water/aqua/eau, alcohol denatured, alcohol, ethanol, octylodecanol, isohexadecane and combinations thereof.
  • the solvent contains more than one solvent is selected from water/ aqua/eau, alcohol denatured, alcohol, ethanol, octylodecanol, or isohexadecane.
  • the solvent is present in an amount of about 35% to about 75% by weight of the topical final formulation.
  • the solvent is water present in an amount of about 35% to about 75% by weight of the topical final formulation.
  • the solvent comprises both water and ethanol present in a total amount of about 55% to about 60% by weight of the topical final formulation.
  • the cosmetically acceptable excipient is selected from the group consisting of a preservative, an antioxidant, a chelator, a filler, a film former, a fragrance, a pH adjuster, and combinations thereof.
  • the cosmetically acceptable excipient is selected from the group consisting of hydroxyacetophenone, ethylhexylglycerin, sodium phytate, tromethamine, lactic acid, disodium phosphate, phenoxyethanol, xylose, HDI/trimethylol hexyllactone crosspolymer, lactose, ethylhexylglycerine, disodium EDTA, mineral salts, glucose, caprylyl glycol, silica, hexylene glycol, sodium benzoate, fragrance/parfum, BHT, hydrated silica, silica dimethyl silylate, sodium citrate, citric acid, lactic acid, sodium hydroxide, VP/
  • the cosmetically acceptable excipient contains more than one excipient is selected from hydroxyacetophenone, ethylhexylglycerin, sodium phytate, tromethamine, lactic acid, disodium phosphate, phenoxyethanol, xylose, HDI/lrimelhylol hexyllactone crosspolymer, lactose, ethylhexylglycerine, disodium EDTA, mineral salts, glucose, caprylyl glycol, silica, hexylene glycol, sodium benzoate, fragrance/parfum, BHT, hydrated silica, silica dimethyl silylate, sodium citrate, citric acid, lactic acid, sodium hydroxide, VP/polycarbamyl polygylcol ester, hydrolyzed sesame protein PG-propyl methylsilanediol, glucose, silica, tocopherol, limonene,
  • the cosmetically acceptable excipient is present in an amount of about 0.1% to about 5% by weight of the topical final formulation. In some embodiments, the cosmetically acceptable excipient is present in an amount of about 1% to about 2% by weight of the topical final formulation.
  • the additive is present in an amount of about 0.1% to about 20% by weight of the topical final formulation.
  • the additive is a cosmetic additive selected from the group consisting of vitamins, cosmetic peptides, oil control agents, sensation modifying agents, skin lightening agents, hydrating formulations, a compound that absorbs or reflects UV photons, other skin care agents, and combinations thereof.
  • the additive is selected from the group consisting of 3-O-ethyl ascorbic acid, niacinamide, retinaldehyde hydroxysomes, retinyl palmitate, hydroxyapatite, whey protein, Pyrus Malus (apple) fruit extract, calcium PCA, magnesium PCA, retinal, sea salt/maris sal/sel marin, glaucine, adenosine, ceramide NP, cholesterol, ceramide NS, ceramide AP, ceramide EOP, ceramide EOS, caprooyl phytosphingosine, caprooyl sphingosine, ascorbyl palmitate, tocopherol, glycoin, hyaluronic acid, hyaluronic acid derivative, and combinations thereof.
  • the additive is glaucine, which promotes fat breakdown and reduces the appearance of double chin and improves contours of the neck and chin.
  • the additive is a combination of stacked retinoinds, melanosome transfer inhibitor and vitamin C, wherein the stacked retinoids are selected from retinaldehyde hydroxysomes, retinyl palmitate, retinal, or combinations thereof, which targets photodamaged and hyperpigmented skin.
  • the skin is the skin of the decolletage.
  • the vitamin selected as a cosmetic additive is selected from the group consisting of vitamin D, vitamin K, vitamin B (including niacinamide, nicotinic acid, Ci-is nicotinic acid esters, and nicotinyl alcohol; B6 compounds, such as pyroxidine; and B5 compounds, such as panthenol, or “pro-B5”), vitamin A (including retinoids such as retinyl propionate, carotenoids, and other compounds), vitamin E (including tocopherol sorbate, tocopherol acetate, other esters of tocopherol), vitamin C (including ascorbyl esters of fatty acids, and ascorbic acid derivatives, for example, ascorbyl glucoside, magnesium ascorbyl phosphate, sodium ascorbyl phosphate, and ascorbyl sorbate), and all natural and/or synthetic analogs thereof, and combinations thereof.
  • vitamin D including niacinamide, nicotinic acid, Ci-is
  • the topical final formulations may comprise about 0.0001 wt. % to about 20 wt. %, about 0.001 wt. % to about 10 wt. %, about 0.01 wt. % to about 5 wt. %, or about 0.1 wt. % to about 1 wt. %, or any individual concentration or range of each vitamin contained in the topical final formulation.
  • the additive is selected from cosmetic peptides selected from the group consisting of di-, tri-, tetra-, penta-, and hexa-peptides, their salts, isomers, derivatives, and mixtures thereof.
  • useful peptide derivatives include, but are not limited to, peptides derived from soy proteins, palmitoyl-lysine-threonine (pal- KT), palmitoyl-lysine-threonine-threonine-lysine-serine (MATRIXYL®), palmitoyl-glycine- glutamine-proline-arginine (RIGIN®), acetyl dipeptide-1 cetyl ester (IDEALIFTTM), and Cu- histidine-glycine-glycine (Cu-HGG, also known as IAMIN®), and naturally occurring and synthesized derivatives thereof, and combinations thereof.
  • Some of the peptides are available from Sederma, France.
  • the topical final formulations may comprise about 1 x 10’ 7 wt. % to about 20 wt. %, about 1 x 10’ 6 wt. % to about 10 wt. %, and about 1 x 10’ 5 wt. % to about 5 wt. %, or any individual concentration or range of each peptide contained in the topical final formulation.
  • the additive is selected from oil control agents selected from the group consisting of compounds useful for regulating the production of skin oil, or sebum, and for improving the appearance of oily skin.
  • oil control agents include, for example, salicylic acid, dehydroacetic acid, benzoyl peroxide, vitamin B3 (for example, niacinamide), and the like, their isomers, esters, salts and derivatives, and mixtures thereof.
  • the topical final formulation of such embodiments may comprise about 0.0001 wt. % to about 15 wt. %, about 0.01 wt. % to about 10 wt. %, about 0.1 wt. % to about 5 wt. %, and about 0.2 wt. % to about 2 wt. %, or any individual concentration or range of each oil control agent contained in the topical final formulation.
  • the additive is selected from other skin care agents selected from the group consisting of retinol, steroids, salicylate, minocycline, antifungals, peptides, antibodies, lidocaine, and the like and combinations thereof.
  • other skin care agents include N-acyl amino acid compounds comprising, for example, N- acyl phenylalanine, N-acyl tyrosine, and the like, their isomers, comprising their D and L isomers, salts, derivatives, and mixtures thereof.
  • An example of a suitable N-acyl amino acid is N-undecylenoyl-L-phenylalanine is commercially available under the tradename SEPIWHITE®.
  • skin active agents include, but are not limited to, Lavandox, Thallasine 2, Argireline NP, Gatuline In-Tense and Gatuline Expression, Myoxinol LS 9736, Syn-ake, and Instensyl®, SesaflashTM, N- acetyl D-glucosamine, panthenol (for example, DL panthenol available from Alps Pharmaceutical Inc.), tocopheryl nicotinate, benzoyl peroxide, 3-hydroxy benzoic acid, flavonoids (for example, flavanone, chaicone), famesol, phytantriol, glycolic acid, lactic acid, 4-hydroxy benzoic acid, acetyl salicylic acid, 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, cis- retinoic acid, trans-retinoic acid, retinol, retinyl esters (for example, retinyl propionate),
  • the additive is a cellulite treatment agent.
  • the cellulite treatment agent is selected from the group consisting of apigenin, extracts containing Berberine or salts thereof, a blend of pterostilbene (resveratrol dimethyl ether) and xymenynic acid dissolved in glyceryl linoleate and glyceryl linolenate, and combinations thereof.
  • the additive is a skin lightening agent or an antiaging ingredient selected from the group consisting of ascorbic acid compounds, vitamin B3 compounds, azelaic acid, butyl hydroxy anisole, gallic acid and its derivatives, glycyrrhizinic acid, hydroquinone, kojic acid, arbutin, mulberry extract, and combinations thereof.
  • the topical final formulation may comprise Ovaliss ((S)- 5,6,6a,7-Tetrahydro-l,2,9,10-tetramethoxy-6-methyl-4H-dibenzo[de,g]quinoline, 1,2- Octanediol, D-Glucopyranose, oligomeric, C10-16-alkyl glycosides, water, ethyl alcohol, and glycerin), Whey protein, MPC (Milk protein complex), Sesaflash (Glycerin, Acrylates copolymer, PVP/polycarbamyl polyglycol ester, Hydrolyzed Sesame Protein PG - propyl methylsilanediol), Majestem (glycerin, Leontopodium Alpinum Callus Culture Extract and xanthan gum), Idealift (butylene glycol, sorbitan laurate, hydroxyethylcellulose, and acetyl dipeptide- 1 cety
  • the topical final formulation may further comprise an emollient or lubricating vehicle that help hydrate the skin can also be used.
  • the emollient is selected from the group consisting of dimethicone, isononyl isononanoate, cetyl ethylhexanoate, Jojoba Esters, cyclopentasiloxane, Helianthus Annuus (Sunflower) Seed Wax, Helianthus Annuus (Sunflower) Seed oil, caprylic/capric triglyceride, Acacia Decurrens Flower Wax, Poly glycerin- 3, glycerin, diglycerin, Butyrospermum Parkii (Shea) Butter, petrolatum, petrolatum plus volatile silicones, lanolin, cold cream (USP), hydrophilic ointment (USP), and combinations thereof.
  • the emollient is present in an amount of about 2% to about 20% by weight of the topical final formulation. In some embodiments, the emollient is present in an amount of about 12% to about 18% by weight of the topical final formulation.
  • the topical final formulation may further comprise an elastomer selected from the group consisting of dimethicone/vinyl dimethicone crosspolymer, polysilicone-11, and combinations thereof.
  • the elastomer is present in an amount of about 0.1% to about 1% by weight of the topical final formulation. In some embodiments, the elastomer is present in an amount of about 0.2% to about 0.4% by weight of the topical final formulation.
  • the topical final formulation may further comprise an emulsifier or surfactant selected from the group consisting of octyldodecanol, octyldodecyl xyloside, PEG-30, dipolyhydroxystearate, polysorbate 80, sorbitan oleate, C14- 22 alcohols, C12-20 alkyl glucoside, cetearyl alcohol, cetearyl glucoside, glyceryl glucoside, potassium cetyl phosphate, bis-PEG-12 demethicone, lecithin, decyl glucoside, ceteareth-25, cetyl alcohol, behenic acid, coco-glucoside, and combinations thereof.
  • an emulsifier or surfactant selected from the group consisting of octyldodecanol, octyldodecyl xyloside, PEG-30, dipolyhydroxystearate, polysorbate 80, sorbit
  • the emulsifier is present in an amount of about 0.5% to about 10% by weight of the topical final formulation. In some embodiments, the emulsifier is present in an amount of about 3% to about 7% by weight of the topical final formulation.
  • the topical final formulation may further comprise a gelling agent selected from the group consisting of acrylamide/sodium acrylpyldimethyl taurate copolymer, sodium acrylpyldimethyl taurate, sodium acrylates copolymer, sodium polyacrylate, carbomer, cetyl hydroxyethylcellulose, gellan gum, and combinations thereof.
  • the gelling agent is present in an amount of about 0.1% to about 5% by weight of the topical final formulation. In some embodiments, the gelling agent is present in an amount of about 0.2% to about 0.6% by weight of the topical final formulation.
  • the topical final formulation may further comprise a humectant selected from the group consisting of glycerin, diglycerin, sodium acetylated hyaluronate, pentylene glycol, hexylene glycol, sodium hyaluronate, and combinations thereof.
  • the humectant is present in an amount of about 2% to about 10% by weight of the topical final formulation. In some embodiments, the humectant is present in an amount of about 4% to about 7% by weight of the topical final formulation.
  • the topical final formulation may further comprise a sensation modifying agent selected from the group of a cooling agent, a warming agent, a relaxing or soothing agent, a stimulating or refreshing agent, and combinations thereof.
  • the topical final formulation may further comprise a cooling agent is selected from but not limited to menthol; an isomer of menthol, a menthol derivative; 4-Methyl-3-(l-pyrrolidinyl)-2[5H]-furanone; WS-23, Icilin, Icilin Unilever Analog, 5-methyl-4-(l-pyrrolidinyl)-3-[2H]-furanone; 4,5-dimethyl-3-(l-pyrrolidinyl)-2[5H]- furanone; isopulegol, 3-(l-menthoxy)propane-l,2-diol, 3-(l-menthoxy)-2-methylpropane-l,2- diol, p-menthane-2,3-diol, p-menthane-3,8-diol, 6-isopropyl-9-methyl-l,4-dioxas- piro[4,5]decane-2
  • a cooling agent is selected
  • the topical final formulation may further comprise a warming agent is selected from but not limited to polyhydric alcohols, capsaicin, capsicum powder, a capsicum tincture, capsicum extract, capsaicin, hamamalis, homocapsaicin, homodihydrocapsaicin, nonanoyl vanillyl amide, nonanoic acid vanillyl ether, vanillyl alcohol alkyl ether derivatives, such as vanillyl ethyl ether, vanillyl butyl ether, vanillyl pentyl ether, and vanillyl hexyl ether, iso vanillyl alcohol alkyl ethers, ethyl vanillyl alcohol alkyl ethers, veratryl alcohol derivatives, substituted benzyl alcohol derivatives, substituted benzyl alcohol alkyl ethers, vanillin propylene glycol acetal, ethylvanillin prop
  • the topical final formulation may further comprise a relaxing or soothing agent is selected from but not limited to herb extracts, selected from the group consisting of aloe vera, alpha bisabolol, D-panthenol, allantoin, hamamelis, chamomile, yarrow; calendula, comfrey, witch hazel and other astringents, sea weed, and oat extracts; oils, selected from the group consisting of: almond oil, avocado oil, and comfrey; and essential oils, selected from the group consisting of: cardamone, eucalyptus, mentha piperita (peppermint), hyssop, and rosemary; waxy or unctuous substances selected from the group consisting of: lanolin or petroleum jelly, minerals, selected from the group consisting of: zinc oxide, calamine and selenium; vitamins, selected from the group consisting of: tocopheryl acetate (vitamin E).
  • herb extracts selected from the group consisting of
  • the topical final formulation may further comprise a stimulating or refreshing agent is selected from but not limited to an alcohol, L-menthol, camphor, menthe oil, capsicum extract, capsaicin, benzyl nicotinate, salicylate, glycol salicylate, acetyl choline, serotonin, histamine, a prostaglandin, a neurotransmitter; a CNS stimulant, caffeine and quinine.
  • a stimulating or refreshing agent is selected from but not limited to an alcohol, L-menthol, camphor, menthe oil, capsicum extract, capsaicin, benzyl nicotinate, salicylate, glycol salicylate, acetyl choline, serotonin, histamine, a prostaglandin, a neurotransmitter; a CNS stimulant, caffeine and quinine.
  • the topical final formulation has a pH of about 5 to about 7.
  • the topical final formulation described herein may be formulated as a liquid.
  • Liquid dosage forms for topical administration may comprise diluents such as, for example, alcohols, glycols, oils, water, and the like. Such compositions may also include wetting agents.
  • the topical final formulation described herein may be formulated into an oil-in-water or water-in-oil emulsion.
  • a cream can be a water-in-oil (w/o) emulsion in which an aqueous phase is dispersed in an oil phase, or an oil-in-water (o/w) emulsion in which an oil is dispersed within an aqueous base.
  • An ointment generally refers to a more viscous oil-in-water cream. Traditional ointment bases (/. ⁇ ?.
  • compositions described above can be formed by the entrapment of large amounts of aqueous or aqueous-alcoholic liquids in a network of polymers or of colloidal solid particles.
  • Such polymers or colloids are typically present at concentrations of less than 10% w/w and include carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium alginate, alginic acid, pectin, tragacanth, carrageen, agar, clays, aluminum silicate, carbomers, and the like.
  • the topical final formulation described herein may be formulated as aerosols, in which the composition is dissolved in a propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas, and a co-solvent such ethanol, acetone, hexadecyl alcohol, and the like and combinations thereof.
  • a propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas
  • a co-solvent such ethanol, acetone, hexadecyl alcohol, and the like and combinations thereof.
  • the topical final formulation described herein may be in the form of hydrogels.
  • Hydrogels are typically prepared by cross-linking various monomers and/or polymers to provide a three-dimensional polymer network.
  • polymers include, polyoxyethylene -polypropylene block copolymers, ionic poly saccharides, such as chitosan or sodium alginate, cellulose, and biodegradable polymers, such as poly-lactides (PLA) and poly-glycolides (PGA), butylene succinate (PBS), polyhydroxyalkanoate (PHA), polycaprolactone acid lactone (PCL), polyhydroxybutyrate (PHB), glycolic amyl (PHV), PHB and PHV copolymer (PHBV), and poly lactic acid (PLA)- poly ethylene glycol (PEG) copolymers (PLEG).
  • topical final formulation described herein may be coated on bandages, mixed with bio adhesives, or included in dressings.
  • topical final formulation described herein may be used in combination with a cosmetic device.
  • topical final formulation described herein may be used in combination with a patch.
  • the topical final formulation described herein is part of an anti- aging regimen.
  • Embodiments are directed to methods of improving the look of skin in a human subject in need thereof comprising topically administering to the skin of the subject a topical final formulation as described herein.
  • improving the look of skin is an improvement in a characteristic of the skin.
  • the characteristic of the skin is selected from the group consisting of firmness, elasticity, fine lines and wrinkles, skin texture, skin tone, and any combination thereof.
  • improving the look of the skin results in smoother, firmer, younger-looking skin.
  • improving the look of the skin results in a brighter complexion, improved texture, and even-looking skin.
  • the skin is the neck or decolletage skin of the subject.
  • Embodiments are directed to methods of improving the look of skin of the neck and decolletage in a subject in need thereof comprising topically administering to the skin of the subject a topical final formulation as described herein.
  • Embodiments are directed to methods of improving a keloid scar in a subject in need thereof comprising topically administering to the skin of the subject a topical final formulation as described herein.
  • Embodiments are directed to methods of improving the appearance of aged skin in a subject in need thereof comprising topically administering to the skin of the subject a topical final formulation as described herein.
  • improving the appearance of aged akin includes improvement of sagging or crepey skin on the face, body or neck.
  • improving the appearance of aged skin results in smoother, firmer, younger-looking skin.
  • Embodiments are directed to methods of improving the appearance of various keratinous fibers in a subject in need thereof comprising topically administering to the skin of the subject a topical final formulation as described herein.
  • improving aging skin is an improvement in a characteristic of the skin.
  • the characteristic of the skin is selected from the group consisting of firmness, elasticity, fine lines and wrinkles, skin texture, skin tone, and any combination thereof.
  • improving the look of the skin results in smoother, firmer, younger-looking skin.
  • improving the look of the skin results in a brighter complexion, improved texture, and even-looking skin.
  • the skin is the neck or decolletage skin of the subject.
  • Embodiments are directed to methods of improving the contour of the neck or jawline in skin of a subject in need thereof comprising topically administering to the skin of the subject a topical final formulation as described herein.
  • Embodiments are directed to methods of decreasing the appearance of cellulite in skin of a subject in need thereof comprising topically administering to the skin of the subject a topical final formulation as described herein.
  • Embodiments are directed to methods of increasing expression of an extracellular matrix protein in skin of a subject in need thereof comprising topically administering to the skin of the subject a topical final formulation as described herein.
  • Embodiments are directed to methods of increasing expression of an extracellular matrix protein in a model system based on a cell-based assay using adult human dermal fibroblasts, or in a 3-dimensional reconstructed skin model comprising administering a TPM liposomal composition as described herein.
  • the extracellular matrix protein is selected from, but not limited to, the group consisting of decorin, type I collagen, type III collagen, elastin, hyaluronate, and combinations thereof.
  • the TPM liposomal composition or topical final formulation used for increasing expression of decorin is at a concentration of about 5 pg/mL to about 50 pg/mL.
  • the increased expression or upregulation is in a percentage of about 130 % to about 200%. In some embodiments, the percentage of increased expression or upregulation is statistically significant.
  • decorin is a small cellular or pericellular matrix proteoglycan protein is a component of connective tissue, binds to type I collagen fibrils, and plays a role in matrix assembly. Decorin is an important component of the extracellular matrix.
  • Decorin is a component of connective tissue, binds to type I collagen fibrils, and plays a role in matrix assembly. Decorin appears to influence fibrillogenesis, and also interacts with fibronectin, thrombospondin, the complement component Clq, epidermal growth factor receptor (EGFR) and transforming growth factor-beta (TGF-beta). Keloid scars have decreased decorin expression compared to healthy skin.
  • the primary function of decorin involves regulation during the cell cycle. It has been involved in the regulation of autophagy, of endothelial cell and inhibits angiogenesis.
  • Decorin the main proteoglycan in skin, has a small size with a core protein of approximately 40kDa and one chondroitin sulfate/dermatan sulfate glycosaminoglycan (GAG) chain.
  • the main function of decorin is to regulate the collagen matrix assembly. Decorin is distributed along collagen fibrils with the core protein and the decorin GAG chain controls the distance between the collagen fibrils. Reducing the length of the decorin GAG chain reduces the distance between the collagen fibrils.
  • Age-related changes in decorin are apparent in the GAG chain in respect to the molecular size and sulfate position but not in the core protein. Structural changes in the decorin GAG chain may be involved in changes in collagen matrix assembly during the aging process.
  • the TPM liposomal composition or topical final formulation used for increasing expression of collagens is at a concentration of about 5 pg/mL to about 500 pg/mL. In some embodiments, the increased expression or upregulation is in a percentage of about 110 % to about 130 %.
  • collagen may be selected from collagen type I, collagen type II, collagen type III, collagen type IV, or collagen type V and combinations thereof. In some embodiments, the collagen can be fibrillary collagen or non-fibrillary collagen and combinations thereof. Low molecular weight collagens can be made, for example, by hydrolysis.
  • the TPM liposomal composition or topical final formulation used for increasing expression of elastin is at a concentration of about 5 pg/mL.
  • the increased expression or upregulation is in a percentage of about 130 %. In some embodiments, the percentage of the increased expression or upregulation is statistically significant.
  • elastin is a protein found in connective tissue and allows many tissues in the body to resume their shape after stretching or contracting.
  • the TPM liposomal composition or topical final formulation used for increasing expression of hyaluronate is at a concentration of about 5 pg/mL.
  • the increased expression or upregulation is in a percentage of about 150 %. In some embodiments, the percentage of the increased expression or upregulation is statistically significant.
  • hyaluronate is a salt or ester of hyaluronic acid, and is known to interact with CD44, a receptor for hyaluronic acid-mediated motility (RHAMM), and intercellular adhesion molecule- 1 (ICAM- 1).
  • CD44 is widely distributed throughout the body and mediates cell interaction with hyaluronic acid.
  • ICAM-1 is a metabolic cell surface receptor for hyaluronic acid, and binding of hyaluronic acid to ICAM-1 may contribute to the control of ICAM-1 -mediated inflammatory activation.
  • the topical final formulation can be applied to the skin one, two, three, four, five or more times each day, and application can be carried out for a period of at least 1 month, 2 months, 3 months, 4 months, 6 months, 8 months or 12 months.
  • the topical final formulation may be administered once, as needed, once daily, twice daily, three times a day, once a week, twice a week, every other week, every other day, or the like for one or more dosing cycles.
  • a dosing cycle may comprise administration for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks.
  • a subsequent cycle may begin approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks later.
  • the treatment regime may comprise 1, 2, 3, 4, 5, or 6 cycles, each cycle being spaced apart by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.
  • the methods may comprise a variety of additional steps including, for example, cleaning the surface tissue at the site of applying, abrading, microdermabrasion, toning, and the like.
  • compositions may be prepared by combining together the components of the formulation, as described herein, at a temperature and for a time sufficient to provide a topically acceptable composition.
  • Embodiments are directed to methods for preparing a TPM liposomal composition
  • a lipophilic ingredient with a polar solvent system (such as dimethyl isosorbide (DMI) and pentylene glycol) and heating the resulting mixture to a temperature between about 60°C to about 65°C;
  • a tocopherol phosphate derivative ingredient to the mixture from step a) once temperature reaches about 57.9°C to about 61 °C, heating and maintaining the temperature of the resulting mixture to between about 57.9°C to about 61°C until all contents melted;
  • the method requires that a base is added at step e).
  • one or more ingredient is temperature sensitive.
  • the mixing at step e) is continuous for about 18 to about 22 minutes. In some embodiments, the mixing at step e) is continuous for about 20 minutes.
  • the temperature at step a) is about 60 °C to about 65°C. In some embodiments, the temperature at step b) is about 57.9°C to about 61°C. In some embodiments, the temperature at step c) is about 32°C to about 35°C. In some embodiments, the temperature at step d) is about 38°C to about 40°C. In some embodiments, the temperature at step e) is about 38°C to about 40°C. In certain embodiments, the TPM liposomal composition is added to a final formulation at about 0.1% to about 40% by weight of the topical final formulation, wherein the final formulation additionally includes an additive, water, and a cosmetically acceptable excipient.
  • the final formulation is selected from the group consisting of neck cream, neck lotion, body lotion, body cream, face lotion, face cream, eye lash treatment, hair moisturizer, hair conditioner, cellulite treatment, nail conditioner, gel, emulsion, silicone gel, water gel, oil-in-water emulsion, or water-in-oil emulsion.
  • a tocopherol phosphate mixture (TPM) liposomal composition is formed by a method comprising the steps of: a) mixing, in a first container, a lipophilic ingredient with a polar solvent system and heating the resulting mixture to a temperature of at least about 60°C, b) adding a tocopherol phosphate derivative ingredient to the mixture from step a) and maintaining a temperature sufficient to melt all contents, c) cooling the mixture from step b) to a temperature of from about 32°C to about 35 °C, and, once cooled, adding one or more lipophilic ingredients and ethanol into the cooled mixture, with mixing until complete dissolution, to form a Phase A, d) mixing, in a second container, one or more water soluble ingredients and water at a temperature between about 38 °C to about 40°C to form a Phase B; e) adding Phase A into Phase B and mixing at a temperature between about 38 °C to about 40°C for at least 20 minutes
  • the temperature in step b) is maintained at from about 57.9°C to about 61 °C.
  • the neutralizing base comprises tromethamine.
  • Example 1 Compositions Ex.l-Ex.9.
  • compositions Ex. 1 and Ex. 2 were prepared with various water soluble actives which proceeded without incident into the liposome formation.
  • Composition Ex. 1 can be made using Process 1 and Process 2, as described in Example 4 below.
  • Composition Ex. 1 has 2.7 % TPM, 8 % Ethanol, 2.5% of a combination of three water soluble actives, and two lipophilic soluble ingredients.
  • Composition Ex. 1 has a ratio of ethanol: PG: DMI of 2.59:2.27:1.
  • Composition Ex. 2 has slightly less TPM (2.5%) only a single water soluble active, and ethanol:PG:DMI ratio of 1.71:1.47:1 and three oil soluble ingredients in the liposome phase.
  • increasing the level of dipalmitoyl hydroxyproline in Ex. 2, to more than 1.0% resulted in the formation of a precipitate as observed by optical microscopy (see Table 3) using Process 2. Suggesting a specific range of dipalmitoyl hydroxyproline that can be used to form Ex. 1 and Ex. 2.
  • the formation of the precipitate should be avoided as it may change the aesthetics, performance, efficacy and usage of the final product.
  • Method B Turbidity. Turbidity of samples determined on a Hach TL-23 benchtop turbidity meter.
  • Method C Optical microscopy. Small aliquots of material were taken after the addition of the lipophilic phase to the water phase prior to neutralization and observed under a VWR Optical microscope with or without polarization. Samples were evaluated for the presence or absence of precipitate at 10 X or 40 X magnification.
  • Method G Particle Size, polydispersity. 100 pL of each sample was diluted 1000 times with DI water to obtain a clear to slightly hazy solution. Diluted solutions were vortexed using a VWR Mini Vortexer at a speed setting of 9 for 45 seconds to ensure homogeneity before analysis. Particle Size Measurements. A Brookhaven Zetasizer was used to measure the particle size of each sample. Each sample was measured 5 times and the mean diameter was calculated.
  • Example 2 Effect of Compositions Ex. 1 and Ex. 2 on the level of ECM components.
  • Compositions Ex. 1 and Ex. 2 successfully formed liposomes without precipitate and were therefore evaluated in a cell-based assay to evaluate their effect on the metabolism, proliferation and output of extracellular matrix (ECM) components in adult human dermal fibroblast culture model (Method E, Table 5).
  • Compositions Ex. 1 and Ex. 2 are comparable in efficacy in terms of their activity in this cell-based model system.
  • Macromolecules of interest were quantified either in the soluble state (i.e. decorin, type I collagen, type III collagen, and hyaluronate) or insoluble, on fixed cells (i.e. total insoluble proteins and elastin). Data is corrected for cell number according to Equation 1 (see Method E below).
  • Composition Ex. 1 showed a slight increased expression or upregulation of Type I and Type III Collagen with increasing concentration of the formulation from 5 to 500 pg/mL as well as statistically significant upregulation of elastin and hyaluronian at 5 pg/mL. Unexpectedly, Ex.l showed a very significant increased expression or upregulation of decorin. In this model, Composition Ex.
  • Method E Metabolism, Proliferation and Output of ECM Components in the Adult Human Dermal Fibroblast Culture Model. Test materials were dissolved in sterile cell culture medium at x2 highest concentration tested and samples were added in triplicates to exponentially growing adult human dermal fibroblasts (aHDF; 7,000 cells/well of a 96 well plate; p.7 Cell Applications, San Diego, CA, cat. # 106-05a; lot# 3014). Cultures were maintained in DMEM/10%FBS.
  • Example 3 The effect of Compositions Ex. 1 and Ex. 2 on the level of soluble and insoluble decorin.
  • compositions Ex. 1 and Ex. 2 were tested to further confirm the results for the increased expression or upregulation of decorin. Results presented in Table 4. It was confirmed that both Compositions Ex.l and Ex. 2 were shown to unexpectedly upregulate soluble and insoluble Decorin (see Table 6). Composition Ex. 1 upregulated soluble decorin at low concentrations from 5 to 50 g/mL and Composition Ex. 2 at higher concentrations at 50 pg/mL. In addition, Composition Ex. 1 upregulated insoluble decorin at both 5 and 50 pg/mL with 50 pg/mL showing the most statistically significant result under these conditions. Composition Ex.
  • Ref. 1 is a commercially available pre-neutralized mixture of TPM, containing disodium lauriminodipropionate tocopheryl phosphate.
  • N/A are experimental conditions where there was a >50% decrease in the cell number compared to water-treated control. Statistically significant results in bold, directional results are italicized. Results collected according to Method F, see below.
  • compositions Ex. 1 and Ex. 2 demonstrated that these compositions can be used for treating keloid scars.
  • insoluble decorin is the one deposited and incorporated in the ECM.
  • the soluble fraction may be the combination of newly synthetized protein and proteolyzed fragments.
  • Method F Test materials were dissolved in sterile cell culture medium at x2 highest concentration tested and samples were added in triplicates to exponentially growing adult human dermal fibroblasts (7,000 cells/well of a 96 well plate; p.7 Cell Applications, San Diego, CA, cat.# 106-05a; lot# 3014). Cultures were maintained in DMEM/10%FBS. At the end of the experiment (day 7), decorin was quantified in the cell culture medium (soluble fraction) and on fixed cells (insoluble fraction) by ELISA. Total insoluble (cytoskeletal) proteins were quantified to determine the effect of test materials on cell proliferation (cell numbers or cell #) according to the method described by Voigt et al., 2005.
  • Example 4 Processes for Preparations of Compositions.
  • Phase B In a separate kettle equipped with a propeller blade Phase B was prepared by heating water, water soluble ingredients, and tromethamine to 38-40 °C. Mix thoroughly.
  • Phase A With effective turnover, add Phase A into Phase B (38-40 °C, or at 38.7
  • Phase B In a separate kettle equipped with a propeller blade Phase B was prepared by heating water and water-soluble ingredients to 38-40 °C. Mix thoroughly.
  • Phase A With effective turnover, add Phase A into Phase B (38-40 °C, or at 38.7
  • Phase B In a separate kettle equipped with a propeller blade Phase B was prepared by heating water and water-soluble ingredients to 38-40 °C. Mix thoroughly.
  • Phase A With effective turnover, add Phase A into Phase B (38-40 °C, or at 38.7
  • Process 3 resulted in unwanted precipitates.
  • Phase B In a separate kettle equipped with a propeller blade Phase B was prepared by heating water, add water-soluble ingredients to 38-40 °C. Mix well.
  • Phase A With effective turnover, add Phase A into Phase B (38-40 °C, or at 38.7
  • Phase A was added into Phase B (38-40 °C-at 38.7 °C), mixed 4000
  • Phase A was added into Phase B (38-40 °C-at 38.7 °C), followed by ethanol mixed 4650 RPM 2 min.
  • Example 7 TPM formulations vs. Commercial vesicles/liposomes
  • Free radical scavenging activity was tested of different experimental conditions expressed as % water control.
  • the positive control, ascorbic acid (Ref. 5) reached the expected level of inhibitory activity technically validating the experiments.
  • Ref. 2 is a commercially available liposome containing (RonaCare®): Water, Hydrogenated Lecithin, Dipalmitoyl Hydroxyproline, Lecithin, Phenoxyethanol, Mannitol, Beta-Sitosterol, Linoleic Acid, Tocopherol, and Sodium Ascorbate.
  • Ref. 3 is a commercially available composition containing Water, Alcohol, Lecithin, Disodium Rutinyl Disulfate, Hydroxyproline, Sorbitol, Magnesium Ascorbyl Phosphate, Tocopherol, Ascorbyl Palmitate, Glyceryl Stearate, Glyceryl Oleate, and Citric Acid. Ex.l see Table 1 above.
  • Tests were performed to demonstrate the effect of different experimental conditions on the melanin content in human epidermal melanocytes. Test materials were added to exponentially growing cultures and the experiment was terminated 7 days later.
  • Ref. 2 is a commercially available liposome containing (RonaCare®): Water, Hydrogenated Lecithin, Dipalmitoyl Hydroxyproline, Lecithin, Phenoxyethanol, Mannitol, Beta-Sitosterol, Linoleic Acid, Tocopherol, and Sodium Ascorbate.
  • Ref. 3 is a commercially available composition containing Water, Alcohol, Lecithin, Disodium Rutinyl Disulfate, Hydroxyproline, Sorbitol, Magnesium Ascorbyl Phosphate, Tocopherol, Ascorbyl Palmitate, Glyceryl Stearate, Glyceryl Oleate, and Citric Acid.
  • Ref. 4 is a commercially available composition of Kojic acid. Ex.l see Table 1 above. N/A: data not reported due to the low cell count.
  • Purpose An efficacy evaluation of a Neck Cream featuring mixed Tocopheryl Phosphates (TPM) as an encapsulated delivery system for multiple cosmetic ingredients.
  • TPM Tocopheryl Phosphates
  • Study Design A study of 15 consenting men and women was performed at the Rodan and Fields Skin Research Center in San Ramon, California. Subjects were given an experimental neck cream and advised to apply product in the morning (before sunscreen), and evening without applying any other products to their necks other than sunscreen during the day. At the time points of 4, 8, and 12 Weeks Ultrasound Intensity Scores of impacted areas were measured using Cortex DermaLab Ultrasound module, operating at 10-20 MHz.
  • the Ultrasound Intensity Score illustrates changes in the density of the tissue under the epidermal layer.
  • the intensity score illustrates novel growth and cell proliferation, as opposed to dormant pockets.
  • TPM Tocopheryl Phosphate

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Abstract

Les compositions de divers modes de réalisation comprennent un mélange de phosphate de tocophérol (TPM) comprenant un liposome comportant une bicouche lipidique et un compartiment aqueux interne, un ingrédient lipophile, un système de solvant polaire, un alcool, une base et une phase hydrosoluble, le liposome étant constitué d'un dérivé de phosphate de tocophérol, les ingrédients lipophiles étant piégés dans la bicouche lipophile du liposome, et un ingrédient hydrosoluble étant dissous dans la phase hydrosoluble et se trouvant dans le compartiment interne du liposome. Les méthodes consistent à améliorer l'aspect de la peau, en particulier du cou et du décolleté, à augmenter l'expression des protéines de matrice extracellulaire dans la peau, à atténuer une cicatrice chéloïde chez un sujet et à améliorer la peau âgée. De plus, des procédés de préparation desdites compositions sont décrits dans la description.
PCT/US2022/070171 2021-01-13 2022-01-13 Compositions cosmétiques WO2022155656A1 (fr)

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